This study is investigating the immunology and histopathology of Inflammatory Arthritis in children with Down syndrome. Approximately 110 babies with Down syndrome are born in Ireland each year, making Ireland’s birth rate of children with Down syndrome the highest in Europe. A variety of medical conditions and immunological abnormalities are associated with Down syndrome. Immune dysregulation predisposes children with Down syndrome to high frequencies of haematologic malignancies, increased susceptibility to infections, and, most remarkably, a high incidence of autoimmune diseases, including arthritis. DA is an inflammatory joint condition affecting children with Down syndrome. The NCPR at OLCHC provides care to 40 children with DA, the largest reported cohort worldwide, led by Dr Charlene Foley and Dr Orla Kileen, whose research has demonstrated that the prevalence of DA is 18-21 times greater than Juvenile Idiopathic Arthritis (JIA) (JIA prevalence 1/1000). From a clinical prospective they have also shown that patients with DA have significantly higher restricted joint count (RJC) than that observed in the JIA with erosive joint damage higher in DA (29%) compared with JIA (10%). These data suggest that DA is associated with greater joint damage and functional disability. Given the differing clinical pictures of DA versus JIA, we hypothesised that DA is distinct from JIA in terms of immunology, histolopathology and genetics. To examine these potential underlying mechanisms, a coordinate translational approach between the NCPR (Clinical assessments), Molecular Rheumatology (TCD) (Immunophenotyping/function and histopathology) and CAR-UCD (Genetics) has been established. Biologic samples from matched DA, JIA, T21 and HC patients have been collected, and current ongoing studies involve phenotypic and functional characterisation of specific immune cell populations in the four distinct cohorts, in addition to histopathology and transcriptomics, outputs of which may identify key mechanisms that are distinct in DA. This work is being performed by Dr Charlene Foley, with Dr Mary Canavan and Dr Achilleas Floudas (Molecular Rheumatology, (TCD). The genetics approach is being performed with Prof Gerry Wilson Group CAR-UCD. Determining if DA is distinct from polyarticular JIA will lead to pathogenic insights and potentially improved therapeutic approaches. This project is funded by Down Syndrome Ireland, Arthritis Ireland and the National Children’s Research Centre.